EP0701571B1 - Utilisation de fragments d'anticorps en therapie - Google Patents

Utilisation de fragments d'anticorps en therapie Download PDF

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EP0701571B1
EP0701571B1 EP94917087A EP94917087A EP0701571B1 EP 0701571 B1 EP0701571 B1 EP 0701571B1 EP 94917087 A EP94917087 A EP 94917087A EP 94917087 A EP94917087 A EP 94917087A EP 0701571 B1 EP0701571 B1 EP 0701571B1
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tnfα
fab
igg
patients
treatment
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EP0701571A1 (fr
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John Therapeutic Antibodies Inc Dept. of LANDON
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BTG International Inc
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Therapeutic Antibodies Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'

Definitions

  • the present invention relates to the use of immunoglobulin Fab fragments in therapy.
  • Antibodies are formed as part of the immune response to a microorganism or foreign macromolecule. They are immunoglobulins (Ig) and are used extensively in clinical practice for the diagnosis, monitoring, prevention and treatment of an increasing number of diseases.
  • Ig immunoglobulins
  • the basic unit from which all antibody molecules are formed was elucidated by Porter (1959) Biochem J. 73 , 119-126, using specific proteolytic enzymes.
  • the most important of the immunoglobulins, IgG comprises two heavy and two light chains with the former being coupled at their hinge region by disulphide linkages. Cleavage with papain above these linkages releases two antibody binding fragments (Fab) and a crystalline fragment (Fc) as shown in Figure 1. Cleavage with pepsin, below the hinge results in a somewhat smaller Fc fragment and a single F(ab') 2 fragment with two binding sites as shown in Figure 1.
  • Each Fab fragment contains both a light chain and part of a heavy chain, and includes the sequences responsible for specific binding to a microorganism or foreign macromolecule.
  • the Fc consists of the remainder of the two heavy chains; this is the site to which complement, macrophages and polymorphonuclear white blood cells can bind.
  • the two heavy chains (but not the light chains) are different for each class of antibody ie IgG, IgM, IgA and IgE.
  • IgG is the dominant circulating immunoglobulin in terms of concentration. It consists of a single basic immunoglobulin unit and, characteristically, has a high affinity for its specific antigen. Further details of antibody structure and function are disclosed in Roitt (1991) Essential Immunology, 7th Edition, Blackwell Scientific Publications, Oxford.
  • Microbial pathogens can cause deleterious effects by releasing soluble toxins.
  • soluble toxins include the neurogenic exotoxins released by diphtheria and tetanus bacilli and various endotoxins such as lipopolysaccharide (LPS) from the cell walls of Gram-negative bacteria and peptidoglycans from Gram-positive organisms.
  • LPS lipopolysaccharide
  • peptidoglycans from Gram-positive organisms.
  • exogenous antibodies to soluble antigens were of therapeutic value: the mortality of children with diphtheria was reduced by systemic administration of serum from horses hyperimmunised with diphtheria toxoid.
  • a similar approach was successful in patients with tetanus. Passive immunisation was quickly extended to the victims of snake envenomation by Calmette in 1894, and by others.
  • the development of the septic shock syndrome involves initiators (such as LPS), mediators (including TNF ⁇ , IL-1 and IL-6) and effectors at the cellular level (eg nitric oxide synthase in endothelial cells). All the initiators and mediators are potential antigens; antibodies against these macromolecules can be used for the prevention and treatment of septic shock.
  • initiators such as LPS
  • mediators including TNF ⁇ , IL-1 and IL-6
  • effectors at the cellular level eg nitric oxide synthase in endothelial cells.
  • All the initiators and mediators are potential antigens; antibodies against these macromolecules can be used for the prevention and treatment of septic shock.
  • PcAb polyclonal
  • McAb monoclonal antibodies
  • Fab fragments derived from polyclonal antibodies directed towards TNF ⁇ , are more effective at reducing the effects of TNF than are intact IgG directed towards TNF ⁇ as disclosed in more detail in the Examples.
  • one aspect of the invention provides a method of neutralising TNF ⁇ in a patient benefiting from such neutralising, comprising administering to the patient Fab fragment reactive towards TNF ⁇ .
  • the patient is suffering from septic shock or from the symptoms of septic shock.
  • a further aspect of the invention provides a method of preventing or ameliorating septic shock or the symptoms of septic shock in a patient comprising administering to the patient IgG Fab fragments reactive towards TNF ⁇ .
  • the Fab fragments may be generated from substantially pure IgG reactive towards TNF ⁇ by methods well known in the art and disclosed in the Examples.
  • a further aspect of the invention provides IgG Fab fragments reactive towards TNF ⁇ for use in medicine.
  • a still further aspect of the invention provides use of an IgG Fab fragment reactive towards TNF ⁇ in the manufacture of a medicament for treating patients benefiting from neutralisation of TNF ⁇ .
  • the IgG Fab fragments are derived from polyclonal antiserum.
  • Polyclonal antiserum (which includes polyclonal IgG) can be produced by immunizing a sheep, goat, horse or other mammal. It is preferable if the mammal is a sheep, and that it is free of scrapie and zoonotic viruses. Methods of making Fab fragments reactive towards TNF ⁇ and derived from polyclonal sheep IgG are described in the Examples.
  • Fab fragments reactive towards TNF ⁇ are useful in the treatment of medical conditions characterised by an increase in the level of circulating TNF ⁇ .
  • Such conditions include shock, for example septic shock, and excess TNF ⁇ in the context of tumour therapy.
  • Septic shock may occur following bacterial infection, particularly infection with Gram-negative bacteria, and during septicaemia.
  • shock we also include trauma following an accident or surgery.
  • Further uses include treatment in conjunction with anti-lymphocyte antibody therapy, as taught in WO 89/08460, and in conjunction with cancer chemotherapy, as taught in EP 355 067.
  • OKT3 binds specifically to the CD-3 complex found on all mature T lymphocytes.
  • CD-3 is normally involved in antigen recognition and cell stimulation and both are prevented, due to steric hindrance, by the presence of the murine antibodies.
  • the hybridoma expressing the monoclonal antibody OKT3 is available from the America Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852 USA under accession number ATCC CRL 8001. It is of the IgG2a isotype and reactive to human helper T cell subset.
  • the hydridoma and antibody are cited in US Patent 4,381,295 incorporated herein by reference.
  • a treatment regime with OKT3 is described in Ortho Study Group (1985) N. Engl. J. Med. 313, 337-342 incorporated herein by reference.
  • the IgG Fab fragment reactive towards TNF ⁇ is used to treat patients who are receiving the monoclonal antibody OKT3, or functionally equivalent polyclonal antisera, for example in order to reduce actue rejection during kidney transplantation.
  • the IgG or Fab fragment reactive against TNF ⁇ reduces the shock-like side effects of the treatment with OKT3 or functionally equivalent antibodies.
  • Louse-borne relapsing fever caused by the spirochaete Borrelia recurrentis, has been responsible for massive pandemics in Europe, Africa and the Middle East during this century but it is currently restricted to an endemic focus in the highlands of Ethiopia. During epidemics the mortality of the untreated disease may exceed 40% but is reduced to less than 5% with antimicrobial agents including penicillin, tetracyclines, chloramphenicol and erythromycin. Clinical cure, can only be achieved by the use of antibiotics which induce a violent and sometimes fatal Jarisch-Herxheimer reaction (JHR).
  • JHR Jarisch-Herxheimer reaction
  • Intravenous tetracylcines cause such a reaction which starts predictably within about an hour of treatment and consists of three phases - rigors, flush and defervescence - of the classical "endotoxin" or "shock” reaction (Warrell et al (1970) Clin. Sci. 39 , 123-145. Patients may die during the reaction, either with hyperpyrexia at the peak of the fever during the early part of the flush phase, or of shock or acute myocardial failure during the flush/defervescence phase.
  • IgG Fab fragments reactive towards TNF ⁇ are used to treat patients with symptoms of septic shock as evidenced by the Jarisch-Herxheimer reaction.
  • the JHR is associated with the antibiotic treatment of louse-borne-relapsing fever.
  • JHR or a similar reaction, is associated with antibiotic treatment of various other parasitic and invading organism diseases including syphilis, tick-borne relapsing fever, Vincent's angina, rat-bite fever, leptospirosis, yaws, brucellosis and African trypanosomiasis.
  • JHR of louse-borne relapsing fever provides an ethical model for clinical testing of anti-TNF ⁇ intervention, and that it is well known that an increase in the levels of TNF ⁇ is found in JHR.
  • a further aspect of the invention provides a pharmaceutical composition comprising IgG Fab fragments reactive towards TNF ⁇ and a physiologically tolerable carrier.
  • the IgG Fab fragments may be used whenever one wishes to neutralise TNF ⁇ in a patient.
  • the dose administered will be determined by reference to the weight of the patient and the severity of the condition but, typically, 200-2000 mg of specific anti-TNF ⁇ Fab fragment will be administered to an adult over 2 to 3 days.
  • the Fab fragment is derived from polyclonal antisera and is not affinity purified. 120 mg/kg of total Fab is administered, which contains about 20 mg/kg of specific anti-TNF ⁇ Fab.
  • the Fab fragment is substantially pure and is non-pyrogenic.
  • Fab fragment can be substantially purified using chromatographic techniques such as cation exchange chromatography or affinity chromatography.
  • Preferably the Fab fragment is affinity purified.
  • the IgG Fab fragments of the invention or a formulation thereof may be administered by any conventional systemic method including parenteral (eg intravenous, subcutaneous or intramuscular) injection.
  • the treatment may consist of a single dose or a plurality of doses over a period of time.
  • the IgG Fab fragments of the invention may be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the Fab fragment and not deleterious to the recipients thereof.
  • Formulations of the IgG Fab fragments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the IgG Fab fragment with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
  • Figure 1 is a diagrammatic representation of the structure of an antibody molecule.
  • Figure 2 shows the effect of intact anti-TNF ⁇ antibody on pulmonary artery pressure and lymph flow in the sheep.
  • Figure 3 shows the effect of anti-TNF ⁇ Fab fragments on lipopolysaccharide-induced mortality in the mouse.
  • Figure 4 shows the effect of the concurrent application of anti-TNF ⁇ IgG or Fab and TNF ⁇ on L929 cells.
  • Figure 5 shows the effect of the application of anti-TNF ⁇ IgG or Fab fragments 2 hours after TNF ⁇ treatment.
  • Figure 6 shows the effect of the application of anti-TNF ⁇ IgG or Fab fragments 4 hours after TNF ⁇ treatment.
  • Figure 7 shows the effect of anti-TNF ⁇ Fab fragment or saline on the temperature of the patients, when initial temperature is normal.
  • Figure 8 shows the effect of anti-TNF ⁇ Fab fragment or saline on the temperature of the patients, when initial temperature is elevated.
  • Figure 9 shows the TNF ⁇ peak levels in patients who have been treated with saline, control Fab or anti-TNF ⁇ Fab.
  • the vials should be new, dust free and treated with sialinating fluid 48 hours in advance to prevent adhesion of the immunogen to the vials.
  • Fresh sialinating solution needs to be made up every 24 hours.
  • Sialinating is carried out in the following way:
  • the immunogen is then dissolved in 0.9% saline.
  • the solution is then mixed by end-over-end rotation for a minimum of 30 minutes.
  • the amount of saline used is F as described below.
  • the prepared immunogen solution is aliquoted into vials using sterile pipettes and a Pipetteman (Trademark) device.
  • TNF ⁇ compared with the salt content has to be taken into account when weighing immunogen.
  • Example 2 Immunization. sample and bleed protocol for anti-TNF ⁇ sheep
  • the table gives a year's fortnightly schedule of the immunization dose administered, the volume of bleed and the processing of individual samples or pooled samples for the production sheep immunized against TNF- ⁇ .
  • a sample is taken from each animal prior to primary immunization. This level is the background level in each sheep.
  • Sheep are immunised according to a set schedule with amounts of rhTNf ⁇ selected on the basis of dose response studies and as disclosed in Examples 1 and 2.
  • the sheep are bled aseptically into sterile and pyrogen-free glass bottles; clotting is accelerated by use of a roll-bottle technique; the bottles are centrifuged; and the serum is collected by aspiration in a laminar flow cabinet, subjected to 0.2 ⁇ m filtration and stored at -20°C. Bacterial and pyrogen contamination is prevented and the product is subjected to rigorous quality control.
  • Antisera from different animals are pooled and their immunoglobulins precipitated at 25°C with sodium sulphate to separate them from most other serum proteins including albumin.
  • the immunoglobulins which largely comprise antibodies of the IgG class, are washed with sterile sodium sulphate and resuspended in saline.
  • Papain digestion The next step is cleavage of the antibodies into Fab and Fc using papain activated with cysteine and EDTA. This is carried out under conditions that ensure the complete degradation of intact IgG. The crystalline Fc is removed by centrifugation. The supernatant after papain digestion and centrifugation will contain: (1) specific Fab directed against the soluble antigen of interest; (2) non-specific Fab directed against numerous other epitopes and of no value for therapy; (3) small amounts of protein (including albumin) and other contaminants; and (4) inactivated papain.
  • Affinity Purification Affinity purification of human tumour necrosis factor (anti-TNF) Fab fragment is performed using a cross-linked agarose (Sepharose) medium to which rTNF ⁇ (recombinant human TNF ⁇ ) has been bound. An iso-urea linkage is used to couple the rTNF ⁇ to the medium.
  • All buffers must be sterile and pyrogen free (see SOP 0.2, preparation of sterile, non-pyrogenic buffers for therapeutic manufacture).
  • the required amount of freeze-dried Sepharose powder should be weighed out into a plastic Nalgene bottle and suspended in HCl (ice cold). The gel swells immediately and should be washed for 15 minutes on a sintered glass filter with the same solution (200 ml/g of gel). The solution should be added in several aliquots and the gel should be dried, after the final aliquot, until cracks appear in the surface.
  • the TNF ligand (5 mg/g of gel to be used) should be dissolved in sodium bicarbonate buffer (0.1M, pH 8.3, 7 ml/g of gel to be used) in a plastic Nalgene bottle. Once dissolved, an aliquot (0.25 % of the total) should be taken and then the air dried gel should be added, taking care not to splash the ligand solution from the bottle. The mixture should then be rotated, end over end, at 4°C overnight.
  • Blocking the active groups on the gel after coupling overnight, the gel solution should be transferred back to the glass sinter funnel and the ligand solution aspirated and collected. The gel should then be washed with 200 ml of ethanolamine. All washings should be collected.
  • the gel should then be transferred to a Nalgene bottle containing ethanolamine (1.0M, pH 8.0) and the mixture rotated overnight as before.
  • the blocked gel should be transferred to the sinter funnel and the ethanolamine solution sucked off and collected.
  • the gel should then be washed with coupling buffer (bicarbonate) followed by acetate buffer, then coupling buffer a second time. All washings should be collected.
  • the gel may now be transferred and packed into the column housing and washed thoroughly with saline (0.9%).
  • the coupling efficiency should be determined by measuring the amount of protein in the washings and comparing this with the initial ligand solution aliquot.
  • the Fab solution is circulated at a flow rate of 1 ml/minute for a minimum of two hours at 18°C.
  • the ovine rTNF ⁇ Fab fragment bound to the support is removed by washing the column with glycine (10 mM, pH 2.5).
  • the eluant is collected into citrate buffer (0.6M, pH 8.0: 2.5% final concentration) and stored in Nalgene, 2 liter disposable collection bottles. Samples are taken for QC testing (GF FPLC, pH, protein concentration, sterility and LAL testing).
  • Affinity columns are re-equilibrated using phosphate buffer (10 mM, pH 7.3) until the eluant pH returns to approximately pH 5.5. The column is then equilibrated with saline (0.9%) to prepare for the next cycle.
  • the total Fab solution (in ammonium acetate buffer) is applied to a cation exchange column (BioRad MacroPrep S at present though this may change to a weaker binding column in the future) where the majority of the Fab (>80%) binds.
  • the column, and thereby the bound Fab is then washed with three column volumes of buffer (ammonium acetate pH 4.0) to sanitize the product and remove potential contamination by prion or virus.
  • the bound total Fab is eluted by washing the column with the application buffer containing sodium chloride (0.5M).
  • the eluted Fab is then ultrafiltered and washed with saline to remove ammonium acetate buffer, concentrated as required and pumped into a sterile plastic transfer bag. This bag may be connected directly to the filling machine.
  • the product is terminally filtered, filled and finally filled and lyophilized.
  • the ion exchange column is sanitized between runs using sodium hydroxide (1.0M) and then re-equilibrated with ammonium acetate buffer ready for the next cycle.
  • Figure 5 and especially Figure 6 show totally unexpected results.
  • Fab is considerably more protective than intact IgG. Indeed, delaying the addition of the specific Fab appears to enhance the protective effects.
  • Example 7 Clinical trial of the use of anti-TNF ⁇ Fab fragments to prevent or ameliorate Jarisch-Herxheimer reaction (JHR) after antimicrobial treatment of louse-borne relapsing fever
  • JHR Jarisch-Herxheimer reaction
  • Clinical history including duration of and range of symptoms, and results of physical examination were recorded on a standard pro forma.
  • a polytetrafluorethylene cannula was placed in the antecubital vein, fitted with a three-way tap and kept patent with heparinised saline.
  • a baseline blood sample was drawn for microhaematocrit, total white blood cell count (WBC) spirochaete count, bilirubin, liver enzymes, creatinine or urea.
  • WBC white blood cell count
  • bilirubin bilirubin
  • liver enzymes creatinine or urea
  • a blood culture was set up to detect associated bacterial infections (especially typhoid).
  • a minimum of 30 patients and a maximum of 50 patients are randomised to treatment with either intravenous polyclonal anti-TNF ovine immunoglobulin Fab fragment (ATNF Fab) or an identical-looking placebo (Control Fab). 10 patients received isotonic saline only.
  • ATNF Fab intravenous polyclonal anti-TNF ovine immunoglobulin Fab fragment
  • Control Fab placebo
  • Venous blood will be samples for spirochaete count WBC count and cytokines (TNF ⁇ , IL-1 ⁇ , IL-8 and IL-6) at the following intervals:- -30, 0, 60, 90 min; 2, 4, 8 and 24 hr.
  • the TNF ⁇ antitoxin is an ovine Fab manufactured by immunisation of sheep with human recombinant TNF ⁇ (hrTNF ⁇ ).
  • HrTNF ⁇ is produced in E. coli by expression of a synthetic gene with the sequence based on that of published cDNA for human TNF (commercially available from British Biotechnology).
  • the recombinant protein has a molecular weight of approximately 17.5 kD and is purified to greater than 97% purity. Each lot of immunogen is tested for purity, molecular weight and cytotoxic activity before injection to the sheep. The latter is assessed using an L929 murine connective tissue cell assay.
  • the sheep are either sampled (5 ml) or bled (500-700 ml) via the jugular vein. Blood is transferred to sterile, pyrogen free bottles, allowed to clot (in the case of a 5 ml sample) or gently rolled to initiate and speed clotting (in the case of bleeds). The clot is then centrifuged and the serum (as the supernatant) aspirated via sterilising (0.22 ⁇ m) filters, into gamma irradiated plastic bags.
  • the antibody titre of each sheep in the flock is assessed using a simple enzyme linked immunosorbent assay (ELISA).
  • ELISA enzyme linked immunosorbent assay
  • TNF ⁇ is bound at high pH (9.6) to a solid-phase immunoassay plate (96 well) and increasing dilutions of the serum incubated with it.
  • hrTNF ⁇ -specific antibodies in the serum bind to the plate and any unbound antibody is then washed away.
  • a second antibody, raised in donkeys to sheep immunoglobulin, is then added which has conjugated to it an enzyme (horse radish peroxidase, HRP).
  • HRP catalyses a chromogenic reaction, the product of which is proportional to the concentration of antibody in the sheep serum. Bleeds with a titre greater than 1/30,000 are subsequently combined to form a 10 sheep serum pool. Sheep which fail to achieve this titre are dropped from the flock.
  • Sterility and endotoxin tests are performed on each serum pool which must be sterile and contain less than 1.25 Eu/ml to be used in manufacture. Pooling, and all subsequent manufacturing steps, are performed in clean rooms under class 100 conditions.
  • Pools must contain at least 2 g/l of specific antibody to be used for manufacture.
  • the serum immunoglobulin fraction is separated from other non-therapeutic serum proteins using salt precipitation.
  • sodium sulphate USP grade 36%, 25°C apyrogenic and sterile
  • pooled serum a serum that is mixed with pooled serum, over a 15 minute period, maintaining the temperature at 25°C.
  • the precipitate from this procedure is then pelleted by centrifugation and the supernatant aspirated.
  • the pellet is then washed twice with sterile filtered sodium sulphate solution (18%), concentrating the precipitate after each wash by centrifugation.
  • the final pellet is resuspended in sterile isotonic (0.9%) saline and then sterile (0.2 ⁇ m) filtered.
  • Samples of greater than 85 % purity and with a titre greater than 85 % that of the untreated serum are then used for Fab production.
  • the concentration of the immunoglobulin at this stage is approximately 25 g/l as judged by optical density measurement at 280 nm (using an extinction coefficient of 15, 1% 280 nm for IgG).
  • Fab fragments of the immunoglobulin are prepared by incubation of the purified immunoglobulin with the plant enzyme papain which is itself bound to a solid-phase matrix allowing post digestion removal of the enzyme from the digest mixture.
  • the enzyme matrix is added to the IgG preparation in the presence of the reducing agent cysteine and EDTA (to preserve enzyme activity) and digestion allowed to progress for 24 h at 37°C. After this time the reaction is terminated by centrifugation of the mixture which removes both the immobilised enzyme from solution and the need to add large amounts of iodoacetamide blocking agent.
  • the solution is then ultrafiltered across a 10 kD polysulphone ultrafilter (incorporating a 0.45 ⁇ m glass fibre prefilter) and washed with 10 volumes of saline (0.9%, sterile, apyrogenic) to remove all traces cysteine, EDTA and any Fc fragments. Washing procedures ensure salt contamination levels of below 2 ppm.
  • the sterile, apyrogenic Fab is, finally, filtered through a 0.22 ⁇ m sterilising filter.
  • Samples are removed at this stage for quality assessment and again run on GF FPLC to monitor the efficiency of the digest and small scale affinity purification is also performed to ensure that hrTNF ⁇ -binding ability is not lost during the digestion step.
  • Sterility and LAL tests are also performed at this stage along with spectrophotometric concentration determination.
  • the concentration of Fab, at this stage, is approximately 60 g/l.
  • Vials are reconstituted in water for injection (10 ml).
  • LAL Limulus Amoebocyte Lysate
  • mice and guinea pigs Acute toxicity in mice and guinea pigs.
  • Total WBC was counted using haemacytomer counting chambers.
  • TNF ⁇ , IL-1 ⁇ , IL-8 and IL-6 were measured by immunoassay.
  • Immunoradiometric assay kits for these cytokines were purchased from Medgenix Diagnostics SA, B-6220 Fleurus, Belgium.
  • Figure 9 shows the means of TNF ⁇ peak level in patients treated with anti-TNF ⁇ Fab or control Fab compared to the saline mean.
  • Table 2 also shows the equivalent data for IL-8 and IL-6.
  • TABLE 3 Incidence of Jarisch-Herxheimer reaction Jarisch-Herxheimer rection (J-HR) 0 1+ 2+ 3+ Total J-HR Saline control 2 5 1 2 8 (%) 20 50 10 20 80 Fab control 0 8 10 1 19 (%) 5 40 50 5 95 Anti-TNF ⁇ Fab 10 10 0 0 10 (%) 50 50 0 0 50 Table 3 shows the incidence of Jarisch-Herxheimer reaction in patients treated
  • Example 8 Treatment of patients receiving OKT3 treatment with anti-TNF ⁇ Fab fragments
  • OKT3 is produced from seed lots of the parent hybridoma (ATCC CRL 8001 available from the American Type Culture Collection, 12301 Parklawn Drive, Rockville, MD 20852-1776, USA). The immunoglobulin is purified from ascites and formulated. A treatment regime with OKT3 is described in Ortho Study Group (1985) N. Engl. J. Med. 313 , 337-342.
  • the treatment regime with OKT3 is to inject 5 mg into the patient suffering from rejection of cadaveric renal transplant intravenously over the course of 2 to 4 minutes and to repeat this daily for 10 or 14 days (representing a total of 50 or 70 mg of murine monoclonal antibody).
  • Polyclonal anti-T-lymphocyte antisera (which are not affinity purified) may also be infused intravenously but at a much higher dose (100 to 300 mg) over a longer period (viz about 6 hours). Again such infusions are required daily for 10 to 15 days.)
  • Fab fragments prepared as described in Example 3 or 7. Endogenous TNF levels are 1 ⁇ g/l or less and are confined to the extracellular fluid compartment (about 15 1). A dose of 5 mg or 10 mg of anti-TNF ⁇ Fab fragment is given at the same time as the first dose of OKT3 in order to ameliorate the effect of increased TNF levels and shock symptoms induced by OKT3 treatment.
  • OKT3 and anti-TNF ⁇ Fab fragments Prior to treatment with OKT3 and anti-TNF ⁇ Fab fragments the patient receives conventional immunosuppressives such as daily doses of 1.0 mg per kg of prednisone and 142 mg per kg of azathioprine.
  • OKT3 and anti-TNF ⁇ Fab fragments has started the patient receives daily doses of 0.6 mg per kg of prednisone and 30 mg per kg of azathioprine.

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Claims (4)

  1. Fragments Fab d'IgG dérivés d'une IgG polyclonale réactifs vis-à-vis du TNFα pour utilisation en médecine.
  2. Utilisation de fragments Fab d'IgG dérivés d'une IgG polyclonale réactifs vis-à-vis du TNFα dans la préparation d'un médicament pour traiter des malades bénéficiant de la neutralisation du TNFα.
  3. Utilisation selon la revendication 2 dans laquelle le malade souffre d'un choc septique ou des symptômes du choc septique.
  4. Composition pharmaceutique comprenant des fragments Fab d'IgG réactifs vis-à-vis du TNFα et un support physiologiquement acceptable, dans laquelle les fragments de Fab sont dérivés d'une IgG polyclonale.
EP94917087A 1993-06-03 1994-06-03 Utilisation de fragments d'anticorps en therapie Expired - Lifetime EP0701571B1 (fr)

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